Ectopic ACTH/CRH co-secreting tumors are extremely rare in children and adolescents. The diagnosis of this condition is frequently missed and is sometimes confused with CD due to the effect of CRH on the pituitary.

Paediatric CD is found to have equal distribution between males and females, but male patients present with elevated BMI and potentially shorter height and higher plasma ACTH. There is no significant difference in the cure rate or HPAA recovery time after TSS between males and females.

Objective We reported recently 5 patients with bilateral adrenocortical hyperplasia (BAH) and Cushing syndrome (CS) caused by constitutive activation of the catalytic subunit of protein kinase A (PRKACA). By doing new, in depth analysis of their cytogenetic abnormality, we attempt a better genotype-phenotype correlation of their PRKACA amplification. Design Case series. Methods Molecular cytogenetic, genomic, clinical and histopathologic analyses were performed in 5 patients with CS. Results Reinvestigation of the defects of previously described patients by state-of-the-art molecular cytogenetics showed complex genomic rearrangements in the chromosome 19p13.2p13.12 locus resulting in copy number gains encompassing the entire PRKACA; three patients (one sporadic case and two related cases) were observed with gains consistent with duplications, while two sporadic patients were observed with gains consistent with triplications. Although all five patients presented with ACTH-independent CS, the three sporadic patients had micronodular BAH and underwent bilateral adrenalectomy in early childhood whereas the two related patients, a mother and a son, presented with macronodular BAH as adults. In at least one patient, PRKACA triplication was associated with a more severe phenotype. Conclusions Constitutional chromosomal PRKACA amplification is a recently identified genetic defect associated with CS, a trait that may be inherited in an autosomal dominant manner or occur de novo. Genomic rearrangements can be complex and can result in different copy number states of dosage sensitive genes; e.g. duplication and triplication. PRKACA amplification can lead to variable phenotypes clinically and pathologically, and both micro- and macro-nodular BAH, the latter of which we speculate may depend on the extent of amplification.